Bis-mercaptomercuri derivatives of cyclic-carboxamides and method of preparing same



Patented Mar. 16, 1954 BIS-MERCAPTOMERCURI DERIVATIVES OF CYSLIC-CARBOXAMIDES AND METHOD OF PREPARING SAME Harry L. Yale, New Brunswick, N. J., assignor to Mathieson Chemical Corporation, New York, N. Y., a corporation of Virginia No Drawing. Application November 13, 1951, Serial No. 256,143

This invention relates to, and has for its object, the provision of [A] compounds of the general formula 10 Claims; (01. 260-434) tained by the method essentially comprising interacting compounds of the general formula OR (])R I't-HgOH R-Hgs R" C /CO N Y R-HgOH Y R-HgS-R" z R 2 R (I) wherein Z is a member of the class consisting of 1P 9f g ,,gi g fi fggg fi gg T" Q i the class consisting of hydrogen, alkali metals 3 groups en orgamc (including ammonium) and alkaline-earth metals group R18 alowerialgylene group R is amem' (e. g., calcium); and where the water-soluble her of the class consisting of hydrqgen and19wer' 1'5 salts are desired, one or both of the reactants are 1 2 g 5 15 1 organc ii employed in the water-soluble salt form, or the o e ur mug car on om reaction product is salified in the conventional salts thereof; and [C] method of preparing [A] manner and [B]. These compounds are valuable therapeutic agents especially diuretics v 0 Among the utilizable reactants I are.

The divalent cyclic groups represented by Y H CON[CHzCH(OOH:)OHHgOH]1 include: aromatic radicals (e. g., of benzene, naphthalene); alicyclic radicals (e. g., of cyclohexane, trimethylcyclopentane); and heterocyclic radicals (e. g., of pyridine, furan, thiophene, :0 CH: pyrrolidine).

Among the organic groups represented by R," C OOH are the following: carboxyalkyland esters thereof (e; -CH COOH), iminoalk l g 2 CH y "-0O-NICHzCEKOCHa)CH(CH;)HgOH]:

(B.g.,C

NH and OOOH /NH: H2C CH, I K NaOaG-HC CH-C0-N[CH;CH(0CHa)CH1HgOH]5 NH carboayaminoalkyl- (e. g.,

v cmcnmnncoom OO,N[CHzOH(OH)G H:HgOHh aryl (e. g., o-carboxyphenyland o-methoxy- +0001 phenyl-), and heterocyclic (e. g., C-thiazolylsand C-pyrimidyls-). Y

The invention comprises especially water-solu- (3H1 ble salts of compounds of the general formula /CCOONa O(lower-alkyl) 32C! lw 0H,- H-cm-H -s-cm-cooH mo OO-N CHCON[CHaOH(OCaH5)CHzHg0H]| x 0H2-CHCH2 HE S CH2COOH z :O---(1ower-alkyl) v C0N[OH:OH (0OH;)OHzHg0lEl]a wherein X is a divalent mono-carbocyclic radical. H 0H 0 O 0N8 The compounds-of this invention may "be 0hworm: oiNa -O CHzGOONa Among the utilizable reactants .II are: potassium ethylxanthate, sodium thioacetate, sodium thioglycollate, thiourea, N-methyl thiourea, thioacetamide, thiouracil, and sodium thiobarbiturate.

The following examples 'are illustrative of the invention:

Trisodium salt of o-{[bis-(v-carboxymethylmercaptomercuri p methomy)propyllcarbamyl} phenomyacetic acid a. N,N-diallylacetylsalicyZamide.-To a stirred..

trate is distilled, and the product distilling at 160177 C./2 mm. collected.

b. N,N-diaZlyZsaZicyZamide.-The product prepared in a is mixed with 200 m1. 5% :aqueous NaOH at room temperature, solution occurring I After about one hour the Within five minutes. mixture is acidified, yielding N,N-dia llylsalicylamide quantitative-" amount and, after .recrystallization from 50% ethanol, the-product melts at about 92-93 C. n

. Z gLtaudmelts-atabout oaa c.

c. o-(N,N diallylcarbamyl phenoxyacetic acid.--A mixture of 31 g. (0.106 mole) of N,N-diallylsalicylamide, 10.0 g. chloracetic acid and 14.5 g. (0.212 mole) of KOI-I in 500 cc. ethanol stirred, refluxed for eight hours, cooled and tfiltered (the K61. which forms weighs about 4.5 g.). The alcoholic filtrate is concentrated to dryness, the residue dissolved in water, and the solution made slightly acid with 10% HCl. The acidified solution is then treated with an excess .of .NaHCQa, and filtered (the insoluble material, weighing about 12 g., is unreacted starting ma- :terial*); and the ifiltrate is acidified, yielding an :oily product.

.11. 'o-{lBis-(ry .hydroxymercuri 3 methory) .propyl]carbamyl}phenoa:yacetic acid.-The oily product obtained in c is taken up in 200 ml. methanol and treated with 38.4 g. (0.12 mole) of mercuric :acetate in 250 ml. methanol; 400 ml. of the methanol solution ='.(A) is poured into 2 liters .of water. The gelatinous precipitate, .of is. lhy- ..droxide of the .-formula is isolated by' centrifuging, and dried.

[When 50 ml. of the 'methanolic solution A is poured into 400 ml. of 2% sodium chloride solutiomthereis (obtained about 53 .5 g. of -.a .crystalline solid which sinters at ahoutatl c. and decomposes at about .140 13;]

e. Trisodium .salt .0 .o-{iEbis-i'y .carborymetkylmercaptomercuri 3 .methary-laarozzullaa r- .bamyfigihenoryacetic acid-1.0 .g. of the [hydroxide obtained in d, 1.3.5 .g. of .normal NaOH, and 250 .ml. Water are stirred until clear, and .then treated with 0.35 .g. 71% sodiumthioglyoolate, 2.7 m1. normal NaOH and water. The clear solutionis clarified .with a filter aid .(e. ,g., 'Hyflo), and freeze-dried; on essay .the product yields .thetollowing results: .N, .139; .S, 6.26; Na, 7.25; andI-Ig, 36.57.

EXAMPLE 2 Trz'sodzum salt of ;p'{ [bis- (y-carboxymethylmercaptomercuri-fl-methomy) propyl] carbamyl,}.cyclohexanecarborylic acid a. Dimeth'yl ester of 1.,4-cyclohe.ranedicarboxylic acid-40 g. dimethyl ester of terephthalic acid [Ber. 37, 2001 (11904)], is reacted with 5 g. platinic oxide and 259m1 pureglacialaceticacid, following the method given in J. Ind. Inst. Sci. 22A, 262-74 "(2939), *to obtain 't-hedimethyl ester ,of lA-cyclohexanedicarboxylic acid.

Tb. Monome'flr'yl .ester .of .1,,4-.cyclohea:anedicarbomyZic acid.-'To 40 g. (0.2 mole) dimethyl ester of 1A-cyclohexanedicarhoxylic acidin .600 ml. of methanol is .added slowly. with stirring, 13.2 a. (0.2 mole) 85% 'KOH 111200 ml. of methanol; and the clear solution isreiiuxed three hours and concentrated :on the steam ihath. The residue is then partitioned between 300 ml. of ether and 200 ml. of water, and the water layer is separated and acidified 'with 20% hydrochloric acid to pH 2.0. After coolinathescl'idis filtered andrecrys- .taliized twice :irom hot "water.;.,;it 'aieie saehout [The'compound can be further purified by recrystallization with 5 ml. carbon tetrachloride per gram of crude compound to give a purer sample of the half ester, melting at about 112-114" C.] 0. Methyl ester of 4-chlorojormyl-cyclohemanecarborcylic acid.A mixture of 27.5. g. of the crude ester preparedin b and 34.5 g. purified thionyl chloride-is allowed to stand overnight, refluxed three hours, and worked up to give about 28.5 g. of the product, boiling at about 105-109 C. at mm. pressure.

cl. Methyl ester of 4-(N,N-diallylcarbamyl)cyclohezcanecarboxylic acid.'-To an ice-cold mixture of 28.1 g. of the ester prepared in c, 200 ml. dry benzene, and 14.2 g. N-methylmorpholineis added 13.6 g. redistilled diallylamine in 50 cc. dry benzene, yielding the methyl ester of 4-(N,N-diallylcarbamyl) cyclohexane-carboxylic acid.

This methyl ester in methanol is treated with KOH in methanol, refluxed, concentrated, dissolved in water, and acidified, yielding l-(N,N-diallylcarbamyl) cyclohexanecarboxylic acid. Using a molar equivalent of th s product in place of the o-(N,N-diallylcarbamy1) phenoxyacetic acid used in Example 1d, there is obtained the trisodium salt of p-{[bis-('y-carboxymethylmercaptomercuri-fi-methoxy) propyl] carbamyl} cyclohexanecarboxylic acid, having the following formula:

OCH: orb-c HCHz-Hg s 0 H20 0 ON;

HC-CON C-COONa EXAMPLE 3 Trz'sodzum salt of o-{[bis-(' -carbowymethylmercaptomercuri p-methoxy) propyl] carbamg l}benzoic acid Using a molar equivalent of the diallylamide of phthalic acid in place of the o-(N,N-diallylcarbamyl) phenoxyacetic acid used in Example 1d, there is obtained a compound having the formula other ways, within the scope of the appended claims.

6 I claim: 1

1. Compounds of the classconsisting of: [A] compounds of the general formula and [B] water-soluble salts thereof, wherein Z is a member of the class consisting of -COOH, -CH2COOH, OCH2COOH and SO3H groups, Y is a divalent cyclic organic group of the group consisting of monocarboxylic and mononuclear heterocyclic, R is a lower-alkylene g roup, R is a member of the class consisting of hydrogen and lower-alkyl groups, and R" is a member of the class consisting of -(lower alkylene)-COOl-I, -(lower alkylene)COO(lower alkyl), --(lower alkylene)imino, aryl, and C pyrimidyl.

" 2. Compounds of the class consisting of: [A] compounds of the general formula and [B] water-soluble salts thereof, wherein Z is a member of the class consisting of -COOH, CH2COOH, O-CH2COOH, and -SO3H groups, X is a divalent mono-carbocyclic radical, R is a lower-alkylene group, R is a member of the group consisting of hydrogen and lower-alkyl groups, and R is a member of the class consisting of (lower alkylene)CO0H, (lower a1kylene)COO(lower alkyl), --(lower alkylene)imino, aryl, and C-pyrimidyl.

3. Compounds of the class consisting of: [A] compounds of the general formula 0-(lower-alky1) -HgS-CH:COOH /OO-N x RHgS-CH:CO0H

Z O-(lower-alkyl) 5. A trialkali-metal salt of a compound of the general formula -O CHaCOOH momma 6. The method which essentially comprises :.-1nteraetingiaa, communal: of 5 the generalgiormulaa with a compound of" the general formula, R"'-Sp-R", wherein Z..isa member-of the class consisting of iGQOI-I, --CH2CQOH,.

amt-603E; groups, Y" is a. divalent. cyclic. or garlicegrounpfi is. albwer-alkylenegroup, R! issa. member-of. theigroup; consisting ofhydrogenrand lowen-alkyl .groups,B' is :an organic group. linked toihe sulfur. thmughia-carbon atoms-thereof, and BL is e, member! of the vclass consisting of. by;- dmgen,.,a1ka,1i metals, and. alkaline earth metals. 7'. The trisodium salt of p-{Ebis-( -carboxy, methxlmencaptomemuri 5-. -..methoxy)lpmpxll carbamylfcyclohexanecarboxylia .acid;

8.1. The; trisodiumz; salt; of: 0&{lbiss-W-caflioxymethylmeroa-ptomemuri 5? methoxwpropyflicanbamyfibenzoicyacid:

siThe; trisodiuxm salts of; N.Nbis(y-canbnxy,=

methylmernaptomercurPfi-methoxymopyllearmphoramiciasidn 10:. The; trisodiumhsaltc of o-{ [bis-e (y -carbonmethylmercaptomercurif -53 -t. methoxy.) propyllcarbamyflphenoxyaicetic:acid';

I-IARR-YiL.v YAEEI.

References. Gited int-the file. of; this.-. patent UNITED: STATES Number Name Date- 13955 713 H'entribket a1;v T311131; 1933 139695357 Christianserretvall Aug; 7; 1934 2300392" Tabern- NOV; 3, 1942 2,557,772 Shelton etali June'-19; 1951 2581397 Feinstone Jan: 9;;1952 250L461, Shelton- Jime24, 17952 FOREIGN: PATENTS a Number Gountry Date;

619,515 GreavBritain' Mar: 10} 1949 

1. COMPOUNDS OF THE CLASS CONSISTING OF: (A) COMPOUNDS OF THE GENERAL FORMULA 